The human Il-2 receptor is being studied to understand critical components of the T cell immune response in normal, neoplastic, and immunodeficient states. When T-cells are activated by antigen, both IL-2 and IL-2 receptor expression are induced. The magnitude and duration of the T-cell immune response are determined by the amount of IL-2 produced, the levels of receptors expressed, and the time course of each event. Three chains of the IL-2 receptor are now known to exist, namely IL- 2Ralpha, IL-2Rbeta, and IL-2Rgamma. Dr. Leonard cloned IL-2Ralpha as a post-doctoral fellow, and his lab discovered IL-2Rbeta and found that mutation of the IL-2Rgamma chain results in X-linked severe combined immunodeficiency (XSCID) in humans. The fact that the phenotype in XSCID is more severe than that found in IL-2 deficient humans and mice led the group to hypothesize and improve that IL-2Rgamma is in fact a common gamma chain (gammac) shared by the IL-24, IL-7, and IL-9 receptors. Moreover, the laboratory has demonstrated that heterodimerization of IL- 2Rbeta and gammac is required for IL_2 signaling. The reason for this is clarified by the observation that IL-2beta and gamma each associates with a distinct Janus family tyrosine kinase (JAK1 and JAK3, respectively for IL-2Rbeta and gammac) and that IL-2 induces the tyrosine phosphorylation and activation of each of these kinases. Thus, the coordination of two distinct kinases appears critical for IL_2 signaling. Truncations of gammac can abrogate its ability to interact with JAK3, and many XSCID patients have gammac truncations that are predicted to disrupt interaction with JAK3. Moreover, we have identified a patient with a moderate X-linked combined immunodeficiency characterized by diminished IL-2 responses whose gammac gene contains a point mutation resulting in a single amino acid change in the cytoplasmic domain. This mutation results in a decrease in JAK3 association. Thus, we hypothesize that JAK3 activation is essential for intrathymic maturation and/or selection of T cells and that XSCID results from gammac mutations that interfere with cytokine binding to gammac and/or the ability of gammac to associate with JAK3. By extension, we hypothesize that JAK3 will be found in some autosomal recessive cases of immunodeficiency that are phenotypically similar to XSCID or XCID. Energies have also focused on the development of gene therapy for XSCID, and both retroviral and adeno associated viral constructs have been made for preliminary evaluation.